The Influence of Mepolizumab on Structural and Inflammatory Cells in Severe Eosinophilic Asthma
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- To investigate molecular changes in the bronchial epithelium that occurs with mepolizumab treatment using RNA sequencing
研究概览
简要总结
The IRIS study aims to investigate the way Mepolizumab affects the structure of the airway cells in patients with Severe Eosinophilic Asthma and how the immune function of these cells changes with treatment. The aim is to take samples of cells from the airways before starting Mepolizumab and after 6 months of treatment. These samples will be taken during a bronchoscopy (a camera test looking into the lungs) and we will analyse these cells in the laboratory. These investigations will allow us to better understand how Mepolizumab affects the cells within the airways.
详细描述
IRIS is a prospective observational study investigating Mepolizumab in the treatment of severe eosinophilic asthma.
Eosinophilic airway inflammation has been implicated in the pathogenesis of asthma and is particularly relevant in severe eosinophilic asthma (SEA), in which standard asthma therapies fail to adequately control the disease. In severe asthma, there is bronchial epithelial damage and loss of tight junction integrity, goblet cell hyperplasia, enhanced collagen generation within the airway wall and impaired innate immune responses. Mepolizumab has been shown to reduce exacerbations and improve disease control in SEA but there are no studies assessing the impact of Mepolizumab on structural airway cell activity and function and airway remodelling processes.
Primary Objective:
To investigate changes within bronchial epithelial cells following completion of 6 months (7 doses) of Mepolizumab using single cell RNA sequencing (scRNA-seq) and Frac-seq (subcellular fractionation and RNA-sequencing).
Secondary Objectives:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of Severe Eosinophilic Asthma (as per Southampton Severe Asthma MDT and based on ATS/ERS consensus criteria)
- •Approved for treatment with Mepolizumab by Southampton Severe Asthma MDT (in accordance with NICE TA 431)
- •Blood eosinophil count is ≥0.3 x109cells/L in preceding 12 months
- •≥4 asthma exacerbations needing systemic steroids in the preceding 12 months
- •Age ≥18 years
- •Able to provide written informed consent
排除标准
- •On maintenance daily oral steroids, asthma immune modulators
- •On long-term systemic antibiotics or antifungal treatment
- •Current smoker or ex-smoker with >10 pack year smoking history
- •Known clinically significant respiratory disorder such as bronchiectasis, interstitial lung disease, allergic bronchopulmonary aspergillosis
- •Currently pregnant or planning pregnancy within the treatment period or breast-feeding
- •History of psychiatric, medical or surgical disorders that in the opinion of the chief investigator may interfere with undergoing a bronchoscopy or may compromise study completion or data collection
- •Current malignancy
- •Alcohol or recreational drug abuse
- •Diagnosis of immunodeficiency requiring treatment
- •Previous bronchial thermoplasty
- •Previous treatment with biological therapy
- •Previously unable to tolerate a bronchoscopy
- •Current or recent (within the last 12 weeks) infection with SARS-CoV-2
- •Unable to provide written informed consent
结局指标
主要结局
To investigate molecular changes in the bronchial epithelium that occurs with mepolizumab treatment using RNA sequencing
时间窗: 36 months
Changes at the level of single cell RNA sequencing will be reported as: 1. Changes in the percentage of cell populations present in the airways 2. Normalised gene counts
次要结局
- Changes in epithelial barrier integrity using transepithelial resistance(36 months)
- Changes in epithelial antiviral responses using interferon and other antiviral gene measurements(36 months)
- Changes in airway remodelling by assessing fibroblasts isolated from bronchial biopsies using RNA sequencing(36 months)
- Changes in airway remodelling by assessing fibroblasts isolated from bronchial biopsies using immunostaining(36 months)
- Evaluate the impact of Mepolizumab on peripheral airways by obtaining bronchoalveolar lavage for RNA sequencing(36 months)
- Evaluate the impact on peripheral airways by obtaining peripheral airway brushings for RNA sequencing(36 months)
- Peripheral airway dysfunction using impulse oscillometry(36 months)
- Changes in fibroblast profile with stimulation and IL-5 inhibition using a range of molecular, cellular, protein and metabolic techniques(24 Months)